Neural tube defects (NTDs) including spina bifida, anencephaly and holoprosencephaly are some of the most common structural birth defects observed in humans. The causes of these NTDs are poorly understood, but it is clear that there are both environmental and genetic components. A major advancement in the prevention of spina bifida and anencephaly came with the realization that the incidence of these NTDs can be significantly reduced by periconceptional folic acid supplementation. Intriguingly, incidence can be reduced even further when folic acid is taken along with a multivitamin; however, the essential other nutrient(s) in multivitamin supplements remain unknown. Our recent data indicate that iron is necessary for neural tube closure suggesting that iron may be one of these important nutrients. Iron plays fundamental roles in cellular metabolism and is required for development and growth of all organisms. Iron deficiency is one of the most common nutritional deficits in women of childbearing age and during pregnancy. Furthermore, low dietary iron intake has been associated with increased NTD risk; however, more definitive evidence that iron is necessary for neural tube closure has been lacking. We generated a novel mouse mutant flatiron (ffe) with a hypomorphic mutation in the gene encoding Ferroportin (Fpn1) essential for transport of iron from the mother to the fetus. Our analysis of an allelic series and conditional Fpn1 mutants demonstrate that NTDs including spina bifida, exencephaly and HPE develop due to reduced iron delivered to the embryo. Experiments proposed here will investigate our novel hypothesis that iron is an essential nutrient needed for neural tube development. The overall goal of these studies is to provide the first evidence of the utility of iron in combination with folic acid in the prevention of NTDs and to elucidate the mechanistic pathways by which deficiency of this important nutrient leads to birth defects. These studies will significantly impact human health by providing new simple and inexpensive treatments to prevent NTDs and will provide necessary preliminary data needed to begin to investigate whether iron deficiency is an important contributing factor in human NTDs and if NTDs can be prevented by iron supplementation.